Diels-Alder reactions of 4-halo masked o-benzoquinones. Experimental and theoretical investigations

Article abstract of DOI:10.1039/c4ob00856a

The studies on [4 + 2] cycloaddition of 4-halo derivatives of 6,6-dimethoxycyclohexa-2,4-dienones known as orthoquinone monoketals/masked o-benzoquinones are described. The 4-fluoro, 4-chloro- and 4-iodo-masked o-benzoquinones were stable enough for their

Full text of DOI:10.1039/c4ob00856a

Organic &
Biomolecular Chemistry
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Diels–Alder reactions of 4-halo masked
o-benzoquinones. Experimental and
theoretical investigations†
Cite this: Org. Biomol. Chem., 2014,
2, 5656
1
Seshi Reddy Surasani, Santosh Kumar Reddy Parumala and Rama Krishna Peddinti*
The studies on [4 + 2] cycloaddition of 4-halo derivatives of 6,6-dimethoxycyclohexa-2,4-dienones
known as orthoquinone monoketals/masked o-benzoquinones are described. The 4-fluoro, 4-chloro-
and 4-iodo-masked o-benzoquinones were stable enough for their isolation and characterization. These
conjugated dienones cycloadded with several electron-deficient and electron-rich dienophiles in a highly
regio- and stereo-selective manner to afford the corresponding halo bicyclo[2.2.2]octenone derivatives in
high to excellent chemical yields. The halo masked o-benzoquinones did not undergo dimerization
under the reaction conditions. To evaluate the observed selectivities of these Diels–Alder reactions, we
have performed quantum mechanical calculations for the reactions between halo masked o-benzo-
quinones and methyl vinyl ketone and ethyl vinyl ether at the B3LYP/6-31G** theory level. The differences
in HOMO and LUMO energy gaps suggest that these reactions can be classified as inverse electron-
demand Diels–Alder reactions. The calculated transition state energies and global electronic indexes sup-
ported the experimentally observed selectivities of the reaction in many cases.
Received 2nd May 2014,
Accepted 19th May 2014
DOI: 10.1039/c4ob00856a
www.rsc.org/obc
Introduction
Oxidative dearomatization of aromatic compounds has been
widely identified as a powerful tactic for the generation of high
levels of molecular complexity from easily accessible starting
materials. Of particular prominence is the dearomatization
1
of methoxyphenols into cyclohexadienone synthons. The
electron-rich aromatic compounds such as 2-methoxy- or 4-
methoxy-phenols, which are nucleophilic in nature, can
undergo oxidative dearomatization to generate electrophilic
intermediates by chemical or electrochemical process. Thus
the oxidation of 2-methoxyphenols in the presence of alcohols
such as methanol generates highly reactive conjugated cyclo-
hexadienones better known as orthobenzoquinone monoketals
or masked o-benzoquinones (MOBs), which can be trapped
often with dienophiles in Diels–Alder reactions to furnish the
adducts with excellent stereo- and regio-selectivity
Scheme 1 Generation and reactivity of masked o-benzoquinones.
2
,3
triquinanes and bicyclo[4.2.2]decenones that are pivotal syn-
thons in the construction of natural products with diverse
(Scheme 1). Liao exploited the Diels–Alder strategy of MOBs
for the synthesis of bicyclo[2.2.2]octenones, oxatricycles,
3
structural nature. The most recent examples of total synthesis
4
based on the MOB strategy are (±)-eremopetasidione, the tetra-
5
cyclic lycopodium alkaloid (±)-magellanine, the sesterpenic
Department of Chemistry, Indian Institute of Technology, Roorkee-247 667,
Uttarakhand, India. E-mail: rkpedfcy@iitr.ernet.in, ramakpeddinti@gmail.com;
Fax: (+) 91 13 3227 3560; Tel: (+) 91 13 3228 5438
6
acids (±)-bilosespenes A and B, polyfunctionalized cis-deca-
7
8
lins, (±)-penicillones A and B, (±)-3β-angeloyloxyfuranoeremo-
†
Electronic supplementary information (ESI) available: NMR data tables, copies
9
philane and (±)-3β methacryloyloxyfuranoeremophilane,
1
13
of H and C NMR spectra, copies of 2D NMR spectra, crystallographic data,
theoretical data and transition state structures and theoretical Cartesian coordi-
nates. CCDC 815225 and 900005. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4ob00856a
1
0
(
±)-annuionone B and (±)-tanarifuranonol, optically active con-
11
duramines, helisorin, helicterin B and helisterculin A, and
12
neolignans.
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The bicyclo[2.2.2]octenone derivatives are versatile synthons guaiacol with diacetoxyiodobenzene (DAIB) in methanol at
and can be converted to various bicyclic and tricyclic inter- 0 °C. Thus a solution of DAIB (1.1 equiv.) in methanol was
3
mediates. Further, bicyclo[2.2.2]octenones experience intri- added to a solution of 4-fluoroguaiacol (1) in methanol at 0 °C
guing and useful photochemical reactions, such as 1,3-acyl under stirring. The solution turned immediately into yellow
1
3
migration and oxa-di-π-methane rearrangement. The most indicating the formation of MOB 5. After 10 min of stirring at
privileged protocol for the synthesis of these bicyclo[2.2.2]octe- the same temperature, the contents were concentrated under
nones is the Diels–Alder reaction of cyclohexa-2,4-dienones vacuum and the residue was subjected to flash chromato-
1
with dienophilic compounds.
graphy on silica gel to furnish a yellow liquid. The H NMR for
The in situ generated MOBs undergo Diels–Alder reactions the sample was recorded. The spectrum revealed no traces of a
with external dienophiles to furnish bicyclo[2.2.2]octenone dimeric compound. Similarly, 4-chloroguaiacol (2) and 4-iodo-
1
4
derivatives in high to excellent chemical yields. In the guaiacol (4) were also oxidized to the corresponding MOBs 6
absence of an external dienophile, these reactive species pos- and 8. The Diels–Alder reaction of the diene 5 with methyl
sessing dienic and dienophilic moieties undergo self-dimeriza- acrylate (MA, 25 equiv.) was carried out at room temperature.
tion through Diels–Alder reactions. The dimerization can be The reaction was complete in 24 h and after usual work-up
hindered by replacing one of the methoxy groups at C-6 by and column chromatographic purification, the cycloadduct 9a
acetoxy functionality. The reactivity of the masked o-benzo- was isolated in an overall yield of 59% in two steps. To shorten
quinones can be modulated by careful substitution on the the process, we then applied a one-pot oxidative ketalization/
carbo-diene system and/or by tuning the substituents on the Diels–Alder protocol by generating the MOB 5 in situ in the
C-6 carbon. The nature of the substituents and substitution presence of the dienophile. Thus the oxidation of methoxy-
pattern is often critical in determining the reactivity and stabi- phenol 1 was performed with slow addition (30 min) of a
lity of these MOBs. The MOBs containing substitution of any methanolic solution of DAIB (1.1 equiv.) in the presence of MA
nature (e.g., alkyl, alkoxy, ester, and halo) at position 5 are (25 equiv.) at 0 °C. After 10 min of time the ice-bath was
1
5
non-dimerizing and stable. The parent MOB derived from removed and the contents were stirred at room temperature for
guaiacol and MOBs bearing electron-withdrawing groups on 24 h (Method A) to isolate the adduct 9a in 61% yield. To gain
position 4 are very reactive and dimerize spontaneously and rapid access to 9a, the MOB 4 was generated at 50 °C in the
1
4
provide the corresponding MOB dimers. The functionalities presence of methyl acrylate (Method B). The reaction was com-
such as alkyl and bulky groups such as tert-butyl and acetal on plete in 1 h and in this process the adduct 9a was isolated in
1
4–16
position 4 retard the dimerization event.
72% yield. Encouraged by results from the reaction of phenol
The substitution of halogen at position 4 is another strategy 1 with MA, we carried out the oxidative ketalization/Diels–
to diminish the MOB self-dimerization. Andersson and Alder reactions of 1 with electron-deficient methyl methacry-
1
7
Berntsson observed the non-dimerizing 4-iodo MOB. Liao late (MMA) and methyl vinyl ketone (MVK) following the pro-
used bromine at position 4 to retard the dimerization and cedure detailed in methods A and B (Scheme 2, Table 1). All
carried out Diels–Alder cycloaddition with dienophiles bearing these adducts 9a–c were obtained as single isomers as indi-
7
1
electron-withdrawing groups. Patrick used fluorine at position cated by the H NMR of the crude reaction mixtures. However,
of MOB during his work on the [4 + 2] cycloaddition reac- not to our surprise, the Diels–Alder reaction of MOB 5 with
4
1
8
tions. In the course of remarkable work on arene oxidations, acrylonitrile (ACN) under similar conditions provided the
Quideau used bromo substitution to isolate stable MOBs. In
our laboratory we have isolated the 4-halo MOBs for their
characterization. During our studies on the Diels–Alder reac-
tion of 4-halo MOBs with a series of electron-deficient and
electron-rich dienophiles for the synthesis of highly selective
halo-substituted bicyclo[2.2.2]octenone derivatives, we did not
observe the dimeric Diels–Alder adducts by self-dimerization
1
9
2
0
2
0b,c
of 4-halo MOBs.
In order to understand the observed selec-
tivities in the Diels–Alder reaction of 4-halo MOBs, we carried
out quantum mechanical DFT calculations. Herein we present
2
0b,c
a detailed account of our studies on the title reactions
together with theoretical treatment for the validation of the
experimental results.
Results and discussion
Intrigued by the non-dimerizing nature of 4-halo MOBs, we
became interested in evaluating the stability of 4-halo MOBs
Scheme 2 Diels–Alder reactions of 4-halo MOBs with electron-
by isolation. As a prelude to this objective, we treated 4-fluoro- deficient dienophiles.
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Table 1 Diels–Alder reactions of halo-MOBs 5, 6 and 8 generated from 65% yield. However, the reaction of 1 in the presence of ethyl
a
4
-halo-guaiacols 1, 2 and 4
vinyl ether or butyl vinyl ether in methanol under oxidative
ketalization/Diels–Alder reaction conditions at room tempera-
ture furnished the corresponding cycloadducts in very low
yields. In contrast, the chloro MOB 6 derived from chlorophe-
nol 2 underwent efficient [4 + 2] cycloaddition with styrene,
dihydrofuran (DHF), ethyl vinyl ether (EVE), butyl vinyl ether
(BVE) and phenyl vinyl sulfide (PVS) to give the adducts 13a–e,
respectively (Scheme 3, Table 2). Though the Diels–Alder reac-
tion between MOB 6 and vinyl acetate (VA) performed at room
4
-Halo-2-
methoxy-
Entry phenol
d
Yield
MOB Dienophile Method /time Product (%)
b
c
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
6
6
6
6
6
6
6
6
8
8
8
8
8
8
8
8
MA
MA
A/24 h
B/1 h
A/24 h
B/1 h
A/24 h
B/1 h
A/24 h
B/1 h
A/24 h
B/1 h
A/24 h
B/1 h
A/24 h
B/1 h
A/24 h
B/1 h
A/44 h
B/1 h
A/47 h
B/1 h
A/28 h
B/1 h
A/24 h
B/1 h
9a
9a
9b
9b
9c
9c
9d
9d
10a
10a
10b
10b
10c
10c
10d
10d
11a
11a
11b
11b
11c
11c
11d
11d
61
72
50
61
89
91
57
60
77
92
64
72
70
78
70
80
80
97
81
90
76
85
91
93
MMA
MMA
MVK
MVK
ACN
ACN
MA
e
e
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
MA
MMA
MMA
MVK
MVK
ACN
ACN
MA
e
e
MA
MMA
MMA
MVK
MVK
ACN
ACN
e
e
a
The reactions were carried out with 1 mmol of halo-guaiacol,
5 mmol of dienophile and 1.1 mmol of DAIB in 10 mL of MeOH.
2
b
Method A: room temperature; Method B: 50 °C (see the Experimental
c
section). Represents the reaction time after the addition of DAIB.
d
e
Yield of pure and isolated products. Mixture of stereoisomers.
Scheme 3 Diels–Alder reactions of halo-MOBs with electron-rich
dienophiles.
cycloadduct 9d as a mixture of endo- and exo-stereoisomers in
a 2.2 : 1 (Method A) ratio. The non-selective Diels–Alder reac-
tions of MOBs with ACN are known in the literature.
To broaden the scope of this reaction, we carried out reac-
2
1
Table 2 Inverse electron-demand Diels–Alder reaction of halo-MOBs
a
tions of 4-chloro and 4-iodoguaiacols (2 and 4) with MA, MMA, 5–8 generated from 4-halo-guaiacols 1–4
MVK and ACN at room temperature as well as at 50 °C
c
4
-Halo
Yield
(%)
(Methods A and B) (Scheme 2). The results are presented in
b
Entry
guaiacol
MOB
Dienophile
Time
Product
Table 1. The yields of the cycloadducts 9a–c–11a–c are compar-
able to those adducts derived from 4-bromo MOB (7) of
1
2
3
4
5
6
7
8
9
1
2
2
2
2
2
2
3
3
3
3
3
3
4
4
4
4
4
4
5
6
6
6
6
6
6
7
7
7
7
7
7
8
8
8
8
8
8
Styrene
Styrene
DHF
EVE
BVE
PVS
20 h
20 h
20 h
2 h
12a
13a
13b
13c
13d
13e
13f
14a
14b
14c
14d
14e
14f
15a
15b
15c
15d
15e
15f
65
89
90
75
82
83
7
b
4
-bromoguaiacol (3). The reactions carried out at 50 °C pro-
vided the products in slightly higher yield. The reactions of
-iodoguaiacol (4) performed at room temperature required
longer reaction times (24–47 h). As in the case of 4-fluoro MOB
5), the reactions of 4-chloro and 4-iodo MOBs (6 and 8) with
4
5 h
20 h
24 h
20 h
20 h
2 h
d
VA
70
(
Styrene
DHF
EVE
BVE
PVS
74
95
77
85
77
ACN furnished the products 10d and 11d as mixtures of endo-
and exo-stereoisomers in 1 : 1.4 and 1.1 : 1 ratios, respectively.
The MOBs are known for their Diels–Alder reactivity both
1
1
1
0
1
2
5 h
20 h
24 h
20 h
20 h
2 h
5 h
20 h
24 h
7
a,14,15b
22
d
with electron-deficient
and electron-rich dienophiles. 13
VA
90
2
2d
22a–c
14
Styrene
DHF
EVE
BVE
PVS
75
85
87
88
91
Plumet
and Liao
reported the inverse electron-demand
1
1
5
6
Diels–Alder (IEDDA) reactions of MOBs. Encouraged by the
results obtained from the Diels–Alder reactions of in situ gen- 17
erated 4-halo MOBs with electron-deficient dienophiles, we
then turned our attention to inverse electron-demand Diels–
Alder reactions of these MOBs. The DAIB mediated oxidation
of 4-fluoro-2-methoxyphenol in the presence of styrene, a con-
1
1
8
9
d
VA
90
a
The reactions were carried out with 0.5 mmol of halo-guaiacol,
0 mmol of dienophile and 0.6 mmol of DAIB in 5 mL of MeOH.
Represents the reaction time after the addition of DAIB. Yields of
1
b
c
d
jugative dienophile, provided the Diels–Alder adduct 12a in pure and isolated products. Mixture of stereoisomers.
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1
13
Scheme 4 Selected H and C chemical shifts (in ppm) of Diels–Alder adducts 12a–15a.
13
temperature was regioselective, it was non-stereoselective. The Table 3 Selected C chemical shifts (in ppm) of Diels–Alder adducts
product 13f was obtained as a 1 : 5 mixture of endo- and exo-
Cycloadducts
C-4
C-5
C-6
isomers. The cycloaddition reactions of in situ generated
4
-bromo and 4-iodo MOBs 7 and 8 with the above dienophiles
F-adducts
41–42
47–48
49–50
51–53
164
97–99
proceeded smoothly to afford the products 14a–e–15a–e in very Cl-adducts
135–137
123–125
93–96
119–122
124–126
133–136
Br-adducts
good to excellent chemical yields with excellent stereo- and
I-adducts
regio-selectivities. The Diels–Alder reactions of VA with MOBs
7
1
and 8 at room temperature produced adducts 14f and 15f as
: 1.2 and 1 : 1.1 mixtures of endo- and exo-isomers, respect-
The substantial downfield shift of C-5 (∼164 ppm) of fluoro
2
ively. The non-selective Diels–Alder reactions of MOBs with VA adducts relative to sp carbon of an olefin can be attributed to
2
3
are known in the literature.
The structures of all the new compounds were assigned on atom. A less pronounced deshielding effect can be seen in
the deshielding effect of strong electronegativity of the fluorine
1
13
the basis of their IR, H NMR (500 MHz) and C NMR chloro cycloadducts (δC-5 up to 137 ppm) due to less electron
125 MHz) and DEPT, and mass spectral analyses. The cycload- withdrawal character of the chlorine atom in comparison with
ducts displayed IR absorptions at 1734–1740 cm , a character- the fluorine atom. The chemical shifts of carbon C-5 of bromo
(
−
1
istic absorption of the carbonyl function of bicyclo[2.2.2]- compounds excellently mirror the almost nullified deshielding
1
octenones derived from MOBs. In the H NMR of adducts effect of the bromine atom due to its increased atomic size
bearing Cl, Br and I substitutions, the vinylic proton resonates and reduced electronegativity. Owing to the well-known ‘heavy-
in the range of 5.97 to 6.66 ppm, whereas those of fluoro atom effect’ of iodine, the monovalent iodocompounds
adducts resonate at 5.28 to 5.36 ppm. In general, the bridge- provide a strong shielding effect on the geminal carbon and
head proton H-1 of C-1, which is situated between the carbonyl this is reflective of the diminished chemical shifts of carbon
carbon C-2 and the vinylic carbon C-6, resonates at higher fre- C-5 of iodo adducts. A marked deshielding effect on carbons
quency in comparison with the bridgehead proton H-4 of C-4. C-4 and C-6 of iodo compounds is apparent on inspection of
Of the two methylene protons on C-8, which is connected to the data.
1
C-4, the H-8a resonates in the range of 1.44–2.11 ppm.
The geminal carbons C-5 of fluoro adducts displayed J
CF
2
The proton H-8b resonates at downfield (2.22–2.61 ppm) coupling constants of about 282 Hz, whereas the J coupling
CF
due to the deshielding effect of methoxy groups on C-3 constants of C-4 and C-6 are in the range of 21 and 9 Hz,
1
3
carbon. In the C NMR of these cycloadducts, the ring carbo- respectively. The carbon C-1 is weakly coupled with fluorine
3
nyl carbon C-2 appears in the range of 199–205 ppm with a J coupling constant of ∼6 Hz. No coupling between
CF
(Scheme 4). The ketal quaternary carbon C-3 appears in the the carbon C-3 and fluorine was observed in most of the fluoro
skeletal range of 93.0–94.2 ppm. Among the bridgehead adducts (Table 4). The listed carbon and fluorine coupling
carbons C-1 and C-4, the former which is positioned next to constants are in complete agreement with the expected values.
the ring carbonyl resonates downfield. The effect of halogen
atoms is clearly visible on the chemical shifts of C-4, C-5 and
C-6. The C-4 appears at around 42, 48, 49 and 52 ppm in Table 4
13
19
C– F coupling constants (in Hz) of fluoro adducts
fluoro, chloro, bromo and iodo adducts, respectively. The
halogen attached quaternary sp carbon C-5 of these com-
Fluoro
adduct
2
1
2
2
3
3
C-5 ( JCF
)
C-4 ( JCF
)
C-6 ( JCF
)
C-1 ( JCF
)
C-3 ( JCF
)
pounds resonates at about 164, 136, 124, 95 ppm, respectively.
2
9
9
9
a
b
c
285.0
282.5
282.5
282.5
21.25
21.25
20.00
22.50
8.75
8.75
10.0
8.75
6.25
6.25
6.25
6.25
2.5
0
0
The sp methine carbon C-6 of these halo-bicyclo[2.2.2]octe-
nones resonates at around 97, 120, 124 and 134 ppm, respect-
ively (Table 3).
12a
0
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The assignments of proton and carbon chemical shifts and tivities of compounds 14e and 15a were further confirmed
stereochemical assignments are based on the collective infor- from the single crystal X-ray structures.
mation collected from proton–proton decoupling experiments,
In order to contribute to a better understanding of the
1
1
DEPT analysis, and 2D NMR experiments such as H– H COSY, influence of halogen atoms on position 4 of MOBs and to vali-
heteronuclear multiple quantum correlation (HSQC), hetero- date the experimentally obtained results, we then performed
nuclear multiple bond correlation (HMBC) and rotational theoretical calculations using density functional theory (DFT)
frame nuclear Overhauser effect spectroscopy (ROESY) with the well-established B3LYP/6-31G** method.
measurements. The data obtained from the 2D NMR exper-
Computational details
iments carried out on samples of Diels–Alder adducts 11c and
1
4c are presented in ESI.† The correlation between protons All the calculations were performed with the GAUSSIAN 09
1
1
24
H –H , H –H and H –H is clearly visible from H– H suite of programs. The geometries of all structures and tran-
1
6
7
8a
8a
8b
COSY spectra. The CH connectivities between C
–H and C –H are revealed by HMQC spectra. The HMBC theory at the B3LYP/6-31G** level. The theory has been
analysis provides diagnostic proton–carbon correlations over shown to reliably predict the results of Diels–Alder and other
1
–H
1
, C
4
–H
4
,
sition states (TSs) were fully optimized with density functional
2
5
26
C
7
7
8
8
2
7
multiple bonds which were found to be extremely helpful in pericyclic reactions. A dielectric constant of 32.6 was used to
the conformation of the structure of the product. simulate the methanolic environment. The stationary points
The Diels–Alder reactions of masked o-benzoquinones are were characterized by frequency calculations in order to verify
highly stereo- and regio-selective and produce a single dia- that the TS had one and only one imaginary frequency. Further,
stereomer. Of the four possible isomers, only the one posses- intrinsic reaction coordinate (IRC) calculations were carried out
sing ortho regiochemistry (the electron-withdrawing/electron- at the same level to authenticate the transition states.
releasing group is adjacent to the octenone carbonyl function)
The regio-selectivity of Diels–Alder cycloaddition reactions
and endo stereochemistry (the electron-withdrawing/electron- of dienic MOBs with dienophiles MA/MVK and methyl vinyl
releasing group is anti to the octenone carbonyl function) was ether/EVE has been analyzed in terms of frontier molecular
1
4,28
formed in the current study (except the reactions with acrylo- orbital (FMO) theory.
nitrile and vinyl acetate). terms of normal- or inverse electron-demand Diels–Alder reac-
The regiochemistry of the Diels–Alder adducts was deduced tions, the calculations were performed on MOBs bearing sub-
To classify these cycloadditions in
1
1
2
from H– H decoupling NMR experiments. The assigned endo stituents such as 4-Me, 4-CO Me, 4-COMe with MA/MVK at
stereochemistry is corroborated by the coupling constants ab initio HF/3-21G* and HF/6-31G* calculations, and border-
between H –H and H –H (Table 5). The data reveal that the line energy gaps were obtained, rendering the prediction com-
7
8b
7
8a
1
4,28
coupling constants between H
–H8b. The larger J value for H
tation of the protons H and H , thus confirming the endo since the experimental results are in good agreement with
7
–H8a are less than those of plicated.
The DFT at the B3LYP level with 6-31G basis set
H
7
7
–H8b reveals the cis orien- studies on Diels–Alder reactions has received much attention
7
8b
2
9,30
stereochemistry of the [4 + 2] cycloadduct. The endo stereo- them.
Consequently, we have calculated the energy levels
chemistry of cycloadducts 11c and 14c was further confirmed of the HOMO and LUMO of halo MOBs and the dienophiles
by ROESY measurements. The assigned ortho and endo selec- MVK and EVE by DFT calculations at the B3LYP/6-31G** level
of theory. The calculated HOMO and LUMO energies of these
4
π and 2π components are provided in ESI.†
The differences between HOMOMOB and LUMOdienophile are
Table 5 Chemical shifts (in ppm) of
H
8a and
H8b and coupling
in the range of 5.15–5.43 and 7.87–8.15 eV for the reactions
involving MVK and EVE, respectively. The differences between
–H8b HOMOdienophile and LUMOMOB are in the range of 3.79–4.22
and 3.14–3.57 eV for the reactions of MVK and EVE, respect-
constants (in Hz) between H –H8a and H
7
7
–H8b of cycloadducts 9–15
Compound
δ
8a
δ
8b
7
JH –H8a
JH
7
9
9
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
a
c
2.11
2.06
2.02
1.92
1.95
1.84
1.89
1.85
1.56
1.55
1.49
1.84
1.55
1.54
1.49
1.81
1.52
1.50
1.48
2.29
2.22
2.34
2.30
2.26
2.24
2.57
2.58
2.46
2.45
2.60
2.56
2.45
2.44
2.60
2.48
2.38
2.36
2.54
5.5
6.0
5.5
6.0
6.0
6.0
7.5
6.5
7.0
6.5
5.0
6.5
6.0
6.5
6.0
6.5
7.0
7.0
5.5
10.0
10.0
10.5
10.0
10.0
10.0
10.5
9.5
8.0
8.0
9.0
9.5
8.5
8.0
9.5
9.5
8.5
8.0
9.5
ively (Table 6). Since the interactions between HOMOdienophile
and LUMOdiene are preferred, these reactions can be classified
as inverse electron-demand Diels–Alder reactions. The differ-
ence in energy gaps (ΔΔE) between two possible interactions is
about 1 eV (with MVK) and about 4.5 eV (with EVE). The lesser
ΔΔE values in the former are expected since both dienes and
dienophiles are electron-deficient. These results indicate that
the 4-halo MOBs undergo inverse electron-demand
Diels–Alder reactions with both electron-rich as well as elec-
tron-deficient dienophiles.
0a
0c
1a
1c
2a
3a
3c
3d
3e
4a
4c
4d
4e
5a
5c
5d
5e
Energies of transition structures
The reactions between (i) halo-MOBs and the electron-
deficient dienophile MVK and (ii) halo-MOBs and the electron-
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v
Table 6 DFT B3LYP/6-31G** energy gaps (E ) between the relevant frontier orbitals for MOBs 5–8 and dienophiles MVK and EVE
NED
IED
Difference (NED − IED)
ΔΔE
Preferred
interaction
Entry
Diene
Dienophile
HOMOMOB–LUMOdienophile
HOMOdienophile–LUMOMOB
1
2
3
4
5
6
7
8
FMOB
ClMOB
BrMOB
IMOB
FMOB
ClMOB
BrMOB
IMOB
MVK
MVK
MVK
MVK
EVE
EVE
EVE
5.153332808
5.224899316
5.204218500
5.430619012
7.86959472
7.941161228
7.920480412
8.146880924
4.215621072
4.121468936
4.126911256
3.787038372
3.569889805
3.475737668
3.481179988
3.141307104
0.93771174
1.10343038
1.07730724
1.64358064
4.29970492
4.46542356
4.43930042
5.00557382
IED
IED
IED
IED
IED
IED
IED
IED
EVE
rich dienophile EVE were selected for theoretical studies. In
The Diels–Alder reactions of MOBs are unique in delivering
the Diels–Alder reaction of MOBs, there are four possible reac- the cycloadducts in a highly stereo- and regio-selective
tion pathways based on the approach of the R group (Ac of MVK manner. In these cycloadditions, the initial bond formation
3
b,28,29
or OEt of EVE) with respect to the carbonyl group of MOB, viz. occurs at C-5 of MOB.
Even in the reactions of halo
ortho/endo, ortho/exo, meta/endo and meta/exo (Fig. 1). We denote MOBs, the same trend was observed. Among the two σ-bonds
the corresponding transition state structures as TS1ON, TS1OX
TS1MN and TS1MX (of reactions with MVK) and TS2ON, TS2OX
,
,
C5–C2′ and C –C being formed, the distance between C of
2
1′
5
MOB and C2′ of the dienophile is less than that of C
2
of MOB
TS2MN and TS2MX (of reactions with EVE), where ON, OX, MN & and C1′ of the dienophile indicating that the initial bond is
MX related to ortho–endo, ortho–exo, meta–endo & meta–exo, being formed at C of MOB. Despite the large asynchronicity
5
respectively. From these TSs, the related minima associated with (ranging from 2.92 to 3.58 for MVK reactions and from 3.18 to
the final products are P1ON, P1OX, P1MN & P1MX (from MVK) and 3.67 for EVE reactions) for the ortho regioisomers, the cyclo-
P2ON, P2OX, P2MN & P2MX (from EVE), respectively.
addition takes place via an asynchronous process, in which
The selected geometric parameters of the calculated TSs are the C-5–C-2′ bond is being formed first, while the C2 and C1′
shown in Fig. 2, and Table 7 presents the calculated values of atoms are not yet being bonded at the TS. On the other hand,
transition state energies and relative energies for stationary the non-expected meta pathway proceeds via a concerted
points. The table also includes information on the distance process, where the two σ-bonds are formed simultaneously,
between bond-forming atoms in dienes and dienophiles in but dissymmetrically.
each case. A schematic representation of the different reaction
pathways for each of the reactions (a) Br-MOB + MVK and ondary orbital interactions (SOI) even for dienophiles bearing
b) Br-MOB + EVE is depicted in Fig. 3. As can be seen from electron-releasing substituents. The geometries of the
The endo preference is generally explained by invoking sec-
(
Table 7, the theory is successful in its predictions. For the ortho–endo TSs displayed distances in the range of 2.92–3.11 Å
cycloaddition reactions of halo MOBs with MA, the theory cor- between C-3/C-4 of MOBs and CvO group of MVK and
rectly predicts that ortho approaches are with minimum poten- 3.19–3.40 Å with the oxygen atom of EVE. These distances
tial energy barrier (PEB) and ortho–endo adducts are the may be sufficient to invoke SOI. Alternatively, the large ortho–
preferred products. The transition states TS1ON-F, TS1ON-Cl, endo preference may be attributed to the existence of a destabi-
3
1
TS1ON-Br & TS1ON-I of ortho–endo adducts are stable over tran- lizing interaction in meta–endo and meta–exo transition
sition states TS1OX-F, TS1OX-Cl, TS1OX-Br & TS1OX-I of ortho–exo states that arises from electrostatic and/or van der Waals
adducts by a large amount of 4.05, 3.19, 3.27 and 4.03 kcal interactions between the R group (e.g., Ac of MVK and OEt of
−
1
mol , respectively. The PEBs of ortho approaches in the reac- EVE) of the dienophile and the halo substituent/methoxy
tion of halo MOBs and EVE are again preferred over the meta group of the ketal function owing to their close proximity. The
approaches. However, the energy barrier between TS2ON and ortho–exo TS also experiences such interactions but to a lesser
TS2OX is less. The ortho–exo approaches TS2OX-Cl and TS2OX-I extent as evidenced from its lower PEB in comparison with
are slightly favoured over their ortho–endo approaches, which those of meta TSs. To obtain better insights into non-stereo-
is against the experimental outcome. The preference of selective Diels–Alder reactions of MOBs with acrylonitrile and
TS2ON-I was regained from TS2OX-I when the calculations were vinyl acetate, we have studied the quantum mechanical calcu-
performed in methanolic medium.
lations for the reactions between (i) 4-chloro MOB and ACN
and (ii) 4-chloro MOB and VA to obtain the PEBs of different
approaches in the transition state. The data (see Table S-16 of
ESI†) suggested that in both cases, the endo approach is less
energetic and the ortho–endo, ortho–exo TSs have comparable
−
1
energies (15.25 & 15.86 kcal mol and 21.80 & 21.19 kcal
−
1
mol for the reactions of ACN and VA, respectively). Thus the
theoretical data support the formation of ortho–endo and
ortho–exo products that are observed experimentally from the
Fig. 1 The four possible transition states for the reaction between
an MOB and a dienophile.
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Fig. 2 Optimized geometries for the transition states of reactions between chloro MOB and (a) MVK and (b) EVE.
Table 7 Total energies (in au) and relative energies (in kcal mol−1) for the transition states corresponding to the cycloaddition reaction between
halo MOBs and MVK/EVE
Cycloaddition with MVK
Cycloaddition with EVE
Rel ene
C
(Å)
5
–Cn′
C
(Å)
2
–Cn′
Rel ene
C
(Å)
5
–Cn′
2
C –Cn′
(Å)
(kcal mol−
)
1
B3LYP/6-31G**
(kcal mol−1)
4-Halo MOB
Config.
B3LYP/6-31G**
ortho–endo
ortho–exo
meta–endo
meta–exo
ortho–endo
ortho–exo
meta–endo
meta–exo
ortho–endo
ortho–exo
meta–endo
meta–exo
ortho–endo
ortho–exo
meta–endo
meta–exo
−866.9401133
−866.9336468
−866.9323442
−866.9251091
−1227.3019549
−1227.2968698
−1227.2942833
−1227.2889173
−3338.812108
−3338.8069004
−3338.8054029
−3338.7988166
−7687.0411318
−7687.034717
−7687.0332597
−7687.0276703
11.93
15.98
16.80
21.34
12.24
15.43
17.05
20.42
11.48
14.75
15.69
19.82
0.99
1.91888
2.03426
2.35963
2.43103
2.02331
2.06667
2.31512
2.38832
2.01599
2.02861
2.31229
2.39481
2.03928
2.25001
2.28616
2.31084
2.78550
2.74058
2.23286
2.17443
2.79346
2.80647
2.21854
2.17023
2.82903
2.74718
2.21997
2.18982
2.80180
3.00372
2.17562
2.07949
−868.1290825
−868.1290204
−868.128417
19.27
19.31
19.69
24.97
17.24
16.66
19.84
24.11
14.88
15.63
18.14
23.68
6.35
1.94055
1.99628
2.41458
2.57943
1.90104
2.03186
2.44226
2.54196
1.95316
2.00415
2.33821
2.51228
1.97379
1.77610
2.23009
2.44381
2.78403
2.87542
2.29710
2.03486
2.75090
2.97621
2.30749
2.06447
2.88237
2.93764
2.22190
2.08551
2.90106
2.76643
2.08860
1.88664
−868.1199958
−1228.4946613
−1228.495579
−1228.4905152
−1228.4837049
−3340.0073707
−3340.0061677
−3340.0021762
−3339.9933393
−7688.2332563
−7688.2334107
−7688.2282164
−7688.2218882
5.02
5.93
9.44
6.26
9.52
13.49
reactions between 4-halo-MOBs and acrylonitrile and 3.06 eV) and the low electrophilicity power of dienophiles
vinyl acetate. (ω = 0.40 to 1.61 eV) indicate the electrophilic nature of MOBs
Global electronic indexes – electronic chemical potential μ, and the nucleophilic nature of dienophiles. The data obtained
chemical hardness η and electrophilicity ω – are useful tools from the condensed Fukui functions suggest that the carbon
+
for understanding the reactivity of molecules in their ground C-5 of MOBs 6–8 has the largest electrophilic activation ( f
k
=
32
+
state. The larger electronic chemical potential of dienophiles 0.14–0.19) in comparison with carbon C-2 ( fk = 0.13–0.15)
(
(
μ = −0.0893 to −0.1511 au) in comparison with that of MOBs and the highest nucleophilic Fukui function of EVE is on C-2′
−
−
k k
μ = −0.1683 to −0.1813 au) indicates that the net charge trans- ( f = 0.27) in comparison with C-1′ ( f = 0.10). This supports
fer is taking place from dienophiles to MOB, which is also sup- the formation of the ortho product as observed experimentally.
portive of the inverse electron-demand Diels–Alder reaction The nucleophilic Fukui functions on the electron-deficient die-
(Table 8). The large electrophilicity power of MOBs (ω = 2.54 to nophile MVK do not support the experimental observation.
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Fig. 3 Schematic representation of the different energy profiles for the reaction between (a) Br-MOB (7) and methyl vinyl ketone (MVK), (b) Br-MOB
7) and ethyl vinyl ether (EVE).
(
which the C-5–C-2′ bond is formed first, while the C-2 and C-1′
atoms are not yet bonded at the TS.
While the Fukui indices suggested the ortho regiochemistry
of adducts from EVE, which is in line with the experimental
Table 8 Global properties of MOBs 5–8 and dienophiles MVK and EVE
Reactant
µ (a.u.)
η (a.u.)
ω (eV)
F MOB (5)
Cl MOB (6)
Br MOB (7)
I MOB (8)
MVK
−0.16831
−0.17135
−0.17087
−0.18128
−0.15108
−0.08930
0.15171
0.15088
0.15032
0.14615
0.19259
0.26868
2.540542
2.647630 observation, the nucleophilic Fukui functions on the electron-
2.642626
3.059298
1.612505
0.403821
deficient dienophile MVK do not support the ortho selectivity.
EVE
Experimental section
General
Conclusion
All reagents were purchased at the highest commercially
quality and used without further purification. Solvents were
purified by standard methods. Yields refer to chromatographi-
cally homogeneous materials, unless otherwise stated.
Reactions were monitored by thin-layer chromatography (TLC)
carried out on 0.25 mm silica gel plates (60F-254) using UV
light as a visualizer or in an iodine chamber. Silica gel (par-
ticle size 100–200 mesh) was used for column chromatography
with ethyl acetate–hexanes as an eluent system. Melting points
are uncorrected.
We have demonstrated that the title 4-halo-orthobenzoquinone
monoketals (X = F, Cl, I) are stable enough for the isolation and
characterization. A practical chemical protocol for the synthesis
of highly substituted bicyclo[2.2.2]octenone derivatives in a
highly regio- and stereo-selective manner from the corres-
ponding 4-haloguaiacols is now available. The assigned regio-
and stereo-selectivities are confirmed by NMR analysis including
1D and 2D NMR experiments and single crystal X-ray analysis.
These reactions can be classified as inverse electron-
demand Diels–Alder reactions since the difference in energy
gaps (ΔΔE) between two possible interactions is about 1 eV
Instrumentation
(
with MVK) and about 4.5 eV (with EVE). These results indicate IR spectra of the compounds are expressed as wavenumbers
−
1
that the 4-halo MOBs undergo inverse electron-demand Diels– (cm ). NMR spectra were recorded in CDCl
Alder reactions with two different types of dienophiles.
3
using TMS as an
1
internal standard. Chemical shifts of H NMR spectra were
The computed energies of transition state structures are given in parts per million with respect to TMS and the coup-
successful in predicting regio- and stereo-selectivity. For the ling constant J was measured in Hz. The signals from the
reactions of halo MOBs with EVE, the theory correctly predicts solvent CDCl , 7.26 (residual CHCl ) and 77.0 ppm, are set as
3
3
1
13
that ortho approaches are with minimum potential energy the reference peaks in H NMR and C NMR spectra, respect-
barrier and ortho–endo adducts are the preferred products. The ively. The following abbreviations were used to explain the
PEBs of ortho approaches in the reaction of halo MOBs and multiplicities: s = singlet, d = doublet, t = triplet, q = quartet,
EVE are again preferred over the meta approaches. Analogous m = multiplet, b = broad, dd = doublet of doublet, ddd =
to MOB Diels–Alder chemistry, the initial bond formation doublet of doublet of doublet, dt = doublet of triplet, qd =
occurs at C-5 of halo MOBs in the current addition reactions. quartet of doublet. Mass spectra were recorded by the electro-
The cycloaddition proceeds via an asynchronous process, in spray ionization method using a quadrupole analyzer.
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Generation of MOBs. To a solution of 4-halo-2-methoxy- 1H), 2.29 (ddd, J = 2.5, 10.0, 13.5 Hz, 1H), 2.11 (ddd, J = 3.0,
1
3
phenol (1 mmol) in anhydrous methanol (4 mL) was added a 5.5, 13.5 Hz, 1H) ppm; C NMR (125 MHz, CDCl ) δ 199.6,
3
solution of DAIB (0.354 mg, 1.1 mmol) in anhydrous methanol 172.6, 165.1 & 162.8 (C-5), 97.1 & 97.0 (C-6), 93.6, 52.3, 50.5,
(
6 mL) over a period of 10 min at 0 °C under a nitrogen atmos- 49.9, 48.2 & 48.1 (C-1), 41.6 & 41.4 (C-4), 39.1, 24.2 ppm; HRMS
+
phere. After 10 min, the ice bath was removed. After the reac- (ESI+) calcd for C H FO Na [M + Na] : 281.0801. Found:
1
2
15
5
tion was complete, the reaction mixture was concentrated 281.0807.
using a rotary evaporator under reduced pressure and the (1S*,4R*,7S*)-3,3-Dimethoxy-5-fluoro-7-methoxycarbonyl-7-
residue was purified by silica gel column flash chromato- methylbicyclo[2.2.2]oct-5-en-2-one (9b). Yield 0.166 g (61%)
graphy with 10% ethyl acetate in hexanes as an eluent to as a viscous liquid; IR (KBr) νmax 1736, 1673, 1455, 1367, 1292,
1120 cm−
1
;
1
H NMR (500 MHz, CDCl
furnish the pure 4-halo masked o-benzoquinone.
,6-Dimethoxy-4-fluorocyclohexa-2,4-dienone
.154 g (89%) as a yellowish liquid; IR (KBr) νmax 1740, 1646, 1H), 3.09 (dd, J = 2.5, 14.0 Hz, 1H), 2.61 (dd, J = 3.5, 14.0 Hz,
3
) δ 5.36–5.33 (m, 1H),
6
(5a). Yield 3.70 (s, 3H), 3.38 (s, 3H), 3.36 (s, 3H), 3.34 (dd, J = 4.0, 7.0 Hz,
0
1
232, 1201, 1105 cm− ; H NMR (500 MHz, CDCl
1
1
) δ 6.81 (ddd, 1H), 1.84 (dd, J = 3.0, 14.0 Hz, 1H), 1.31 (s, 3H) ppm; C NMR
13
3
J = 3.0, 6.5, 10.0 Hz, 1H), 6.08 (dd, J = 6.0, 10.5 Hz, 1H), 5.91 (125 MHz, CDCl ) δ 200.8, 175.7, 165.4 & 163.2 (C-5), 98.9 &
3
13
(
(
1
(
dd, J = 3.0, 11.0 Hz, 1H), 3.36 (s, 6H) ppm; C NMR 98.8 (C-6), 93.9, 54.5 & 54.4 (C-1), 52.3, 50.6, 49.7, 46.8, 41.6 &
125 MHz, CDCl ) δ 193.1 (CvO), 158.2 & 156.2 (C-4), 135.9 & 41.5 (C-4), 30.6, 25.2 ppm; HRMS (ESI+) calcd for C13 Na
35.6 (C-5), 127.5 & 127.4 (C-3), 110.2 & 110.1 (C-2), 92.9 & 92.7 [M + Na] : 295.0958. Found: 295.0956.
C-6), 50.1 (OMe) ppm. (1S*,4R*,7S*)-7-Acetyl-3,3-dimethoxy-5-fluorobicyclo[2.2.2]-
-Chloro-6,6-dimethoxycyclohexa-2,4-dienone (6a). Yield oct-5-en-2-one (9c). Yield 0.222 g (91%) as a viscous liquid; IR
.166 g (88%) as a yellowish liquid; IR (KBr) ν
3
H17FO
5
+
4
−
1
0
1
1744, 1691, (KBr) ν
1741, 1671, 1364, 1162, 1129, 1090, 1067 cm ;
max
max
−
1
1
1
632, 1268, 1108, 1054, 1029 cm ; H NMR (500 MHz, CDCl
3
)
3
H NMR (500 MHz, CDCl ) δ 5.28 (ddd, J = 2.5, 5.0, 7.5 Hz,
δ 6.78 (dd, J = 2.5, 10.5 Hz, 1H), 6.44 (d, J = 2.5 Hz, 1H), 6.05 1H), 3.46 (ddd, J = 2.0, 4.0, 7.0 Hz, 1H), 3.38 (s, 3H), 3.35 (s,
1
3
(
d, J = 10.5 Hz, 1H), 3.37 (s, 6H) ppm; C NMR (125 MHz, 3H), 3.18 (qd, J = 3.0, 14.0 Hz, 1H), 3.04–3.01 (m, 1H), 2.22
CDCl ) δ 192.9 (CvO), 141.4 (C-5), 131.1 (C-4), 130.8 (C-3), (ddd, J = 2.5, 10.0, 13.5 Hz, 1H), 2.19 (s, 3H), 2.06 (ddd, J = 3.0,
3
1
3
1
26.6 (C-2), 92.2 (C-6), 50.2 (OMe) ppm.
,6-Dimethoxy-4-iodocyclohexa-2,4-dienone
.246 g (88%) as a yellowish liquid; IR (KBr) νmax 1743, 1687, 47.8 & 47.7 (C-1), 47.0, 41.6 & 41.5 (C-4), 28.2, 23.1 ppm; HRMS
6.0, 13.5 Hz, 1H) ppm; C NMR (125 MHz, CDCl
3
) δ 205.0,
6
(8a). Yield 199.8, 164.8 & 162.5 (C-5), 96.8 & 96.7 (C-6), 93.8, 50.7, 50.0,
0
1
−1
1
+
615, 1252, 1139, 1061 cm
;
H NMR (500 MHz, CDCl
3
)
4
(ESI+) calcd for C12H15FO Na [M + Na] : 265.0852. Found:
δ 6.99–6.96 (m, 2H), 5.80 (d, J = 9.5 Hz, 1H), 3.37 (s, 6H) ppm. 265.0848.
1
3
C NMR (125 MHz, CDCl
C-3), 126.4 (C-2), 93.3 (C-6), 91.1 (C-4), 50.3 (OMe) ppm.
Method A: To
3
) δ 192.8 (CvO), 147.0 (C-5), 143.9
(1S*,2RS,4R*)-5-Fluoro-8,8-dimethoxy-7-oxobicyclo[2.2.2]oct-
(
5-en-2-yl cyanide (9d). Yield 0.135 g (60%) as a viscous liquid;
1
a
solution of 4-halo-2-methoxyphenol IR (KBr) νmax 2927, 1623 cm−1
;
H NMR (500 MHz, CDCl3)
(
(
1 mmol) and a dienophile (25 mmol) in anhydrous methanol δ 5.54 (sept, J = 7.0 Hz, 1H), 5.40 (sept, J = 3.0 Hz, 1H), 3.86 (s,
4 mL) was added a solution of DAIB (0.354 mg, 1.1 mmol) in 3H), 3.76 (s, 3H), 3.44–3.43 (m, 1H), 3.40 (s, 2H), 3.38 (s, 1H),
anhydrous methanol (6 mL) over a period of 30 min at 0 °C 3.37 (s, 4H), 3.32 (s, 4H), 3.26–3.22 (m, 2H), 3.16–3.14 (m, 1H),
under a nitrogen atmosphere. After 10 min, the ice bath was 2.92 (ddd, J = 3.5, 6.5, 12.0 Hz, 1H), 2.55–2.44 (m, 2H),
removed and the contents were allowed to stir at room temp- 2.17 (ddd, J = 2.5, 7.5, 13.5 Hz, 1H), 1.97 (ddd, J = 4.0, 7.5,
erature for the time specified in Table 1. After the reaction was 13.5 Hz, 1H) ppm.
complete, the reaction mixture was concentrated using a rotary
evaporator under reduced pressure and the residue was puri- bicyclo[2.2.2]oct-5-en-2-one (10a). Yield 0.252 g (92%) as a
fied by silica gel column chromatography with 10% ethyl viscous liquid; IR (KBr) ν 2952, 1734, 1623, 1446, 1325,
(1S*,4R*,7S*)-5-Chloro-3,3-dimethoxy-7-methoxycarbonyl-
max
1298, 1206, 1104 cm− ; H NMR (500 MHz, CDCl
1
1
) δ 6.05 (dd,
acetate in hexanes as an eluent to furnish the cycloadduct.
Method B: To solution of 4-halo-2-methoxyphenol J = 2.5, 7.0 Hz, 1H), 3.71 (s, 3H), 3.57 (dd, J = 2.0, 7.0 Hz, 1H),
3
a
(
(
1 mmol) and a dienophile (25 mmol) in anhydrous methanol 3.39 (s, 3H), 3.35 (s, 3H), 3.24 (q, J = 2.0 Hz, 1H), 3.04 (ddd, J =
4 mL) was added a solution of DAIB (0.354 mg, 1.1 mmol) in 2.0, 6.0, 10.0 Hz, 1H), 2.34 (ddd, J = 3.0, 10.5, 13.5 Hz, 1H),
1
3
anhydrous methanol (6 mL) over a period of 1 h at 50 °C 2.02 (ddd, J = 3.0, 5.5, 13.5 Hz, 1H) ppm; C NMR (125 MHz,
under a nitrogen atmosphere. Stirring was continued for CDCl ) δ 199.2, 172.6, 137.1, 120.4, 93.5, 52.4, 50.8, 50.7, 50.1,
3
another 1 h at the same temperature for the reaction to reach 47.4, 39.0, 24.7 ppm; HRMS (ESI+) calcd for C12
completion. The products were purified in a similar manner as [M + Na] : 297.0500. Found: 297.0496.
H
15ClO
5
Na
+
mentioned in Method A.
1S*,4R*,7S*)-3,3-Dimethoxy-5-fluoro-7-methoxycarbonyl- methylbicyclo[2.2.2]oct-5-en-2-one (10b). Yield 0.208 g (72%)
bicyclo[2.2.2]oct-5-en-2-one (9a). Yield 0.186 g (72%) as a as a white solid: mp 58–60 °C; IR (KBr) νmax 2964, 1737, 1623,
(1S*,4R*,7S*)-5-Chloro-3,3-dimethoxy-7-methoxycarbonyl-7-
(
1
1
viscous liquid; IR (KBr) ν
1739, 1670, 1448, 1361, 1205, 1456, 1378, 1291, 1120 cm− ; H NMR (500 MHz, CDCl ) δ 6.07
max
3
163, 1073 cm− ; H NMR (500 MHz, CDCl
1
1
) δ 5.35–5.31 (m, (dd, J = 2.5, 7.0 Hz, 1H), 3.70 (s, 3H), 3.40 (d, J = 6.5 Hz, 1H), 3.39
H), 3.71 (s, 3H), 3.52 (ddd, J = 2.0, 4.0, 6.5 Hz, 1H), 3.38 (s, (s, 3H), 3.37 (s, 3H), 3.17 (q, J = 2.5 Hz, 1H), 2.52 (dd, J = 3.5, 13.5
H), 3.34 (s, 3H), 3.17 (qd, J = 3.0, 6.0 Hz, 1H), 3.02–3.00 (m, Hz, 1H), 1.90 (dd, J = 2.5, 14.0 Hz, 1H), 1.31 (s, 3H) ppm;
1
1
3
3
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13
3
C NMR (125 MHz, CDCl ) δ 200.4, 175.7, 137.1, 122.2,
(1S*,2RS,4R*)-5-Iodo-8,8-dimethoxy-7-oxobicyclo[2.2.2]oct-5-
9
3.7, 57.2, 52.6, 50.7, 49.8, 47.6, 46.7, 31.9, 25.3 ppm; HRMS en-2-yl cyanide (11d). (All the data given here belong to the
+
(ESI+) calcd for C13
H
17ClO
5
Na [M + Na] : 311.0662. Found: mixture of endo and exo.) Yield 0.310 g (93%) as a viscous
liquid; IR (KBr) νmax 2935, 2240, 1737 cm−
1
;
1
H NMR
311.0655.
(
1S*,4R*,7S*)-7-Acetyl-5-chloro-3,3-dimethoxybicyclo[2.2.2]- (500 MHz, CDCl ) δ 6.77 (dd, J = 2.0, 7.0 Hz, 1H), 6.64 (dd, J =
3
oct-5-en-2-one (10c). Yield 0.202 g (78%) as a viscous liquid; 2.0, 7.0 Hz, 1H), 3.45–3.43 (m, 1H), 3.43–3.41 (m, 1H), 3.40 (s,
IR (KBr) νmax 1741, 1625, 1362, 1131, 1101, 1062 cm−
1
;
3H), 3.39 (s, 3H), 3.38 (s, 3H), 3.37–3.32 (m, 2H), 3.31 (s, 3H),
1
H NMR (500 MHz, CDCl ) δ 6.02 (dd, J = 2.0, 6.5 Hz, 1H), 3.16 (ddd, J = 1.5, 5.5, 9.5 Hz, 1H), 2.92 (ddd, J = 3.5, 7.5,
3
3
.50 (dd, J = 2.0, 7.0 Hz, 1H), 3.39 (s, 3H), 3.36 (s, 3H), 3.25 (q, 14.0 Hz, 1H), 2.45 (ddd, J = 3.0, 10.0, 13.0 Hz, 1H), 2.36 (ddd,
J = 2.5 Hz, 1H), 3.07 (ddd, J = 1.5, 6.5, 10.0 Hz, 1H), 2.30 (ddd, J = 3.0, 10.0, 13.0 Hz, 1H), 2.07 (ddd, J = 2.5, 6.0, 13.5 Hz, 1H),
J = 3.0, 10.0, 13.0 Hz, 1H), 2.18 (s, 3H), 1.92 (ddd, J = 2.5, 6.0, 1.88 (ddd, J = 3.0, 6.0, 13.5 Hz, 1H) ppm.
1
3
1
3.0 Hz, 1H) ppm; C NMR (125 MHz, CDCl
3
) δ 204.9, 199.4,
General procedure for Diels–Alder reaction between 4-halo
1
36.2, 120.4, 93.6, 50.6, 50.3, 50.1, 47.4, 46.9, 28.2, 23.7 ppm; MOBs and electron-rich dienophiles. To a solution of 4-halo-
+
HRMS (ESI+) calcd for C H ClO Na [M + Na] : 281.0557. 2-methoxyphenol (0.5 mmol) in anhydrous methanol (5 mL)
1
2
15
4
Found: 281.0552.
1S*,2RS,4R*)-5-Chloro-8,8-dimethoxy-7-oxobicyclo[2.2.2]oct- atmosphere. After 10 min of stirring, a dienophile (10 mmol)
-en-2-yl cyanide (10d). Yield 0.193 g (80%) as a viscous liquid; was added at the same temperature. Then the temperature was
was added DAIB (0.193 mg, 0.6 mmol) at 0 °C under a nitrogen
(
5
−
1
1
IR (KBr) νmax 2360, 1768 cm
;
H NMR (500 MHz, CDCl
3
)
allowed to rise to RT and stirring was continued until complete
δ 6.22 (dd, J = 2.5, 6.5 Hz, 1H), 6.10 (dd, J = 4.5, 6.5 Hz, 1H), disappearance of MOB (the time specified in Table 2). After the
3
3
5
1
3
.60 (s, 6H), 3.48 (dd, J = 2.0, 7.0 Hz, 1H), 3.47–3.39 (m, 1H), reaction was complete, the reaction mixture was concentrated
.38 (s, 3H), 3.33 (s, 3H), 3.31–3.19 (m, 2H), 3.17 (ddd, J = 2.0, using a rotary evaporator under reduced pressure and the residue
.5, 10.0 Hz, 1H), 2.95–2.93 (m, 1H), 2.54 (ddd, J = 2.5, 10.0, was purified by silica gel column chromatography with 10% ethyl
3.0 1H), 2.49–2.44 (m, 1H), 1.96–1.92 (m, 1H), 1.93 (ddd, J = acetate in hexanes as an eluent to furnish the cycloadduct.
.0, 5.5, 13.5 Hz, 1H) ppm.
1S*,4R*,7S*)-3,3-Dimethoxy-5-iodo-7-methoxycarbonyl- oct-5-en-2-one (12a). Yield 0.088 g (65%) as a white solid:
bicyclo[2.2.2]oct-5-en-2-one (11a). Yield 0.354 g (97%) as a yel- mp 71–73 °C; IR (KBr) ν 1740, 1673, 1454, 1363, 1170,
(1S*,4R*,7S*)-3,3-Dimethoxy-5-fluoro-7-phenylbicyclo[2.2.2]-
(
max
lowish liquid; IR (KBr) νmax 1739, 1638, 1436, 1197, 1097, 1066 cm−
1
;
1
H NMR (500 MHz, CDCl
063 cm−
; H NMR (500 MHz, CDCl ) δ 6.60 (dd, J = 2.5, 7.25–7.22 (m, 1H), 7.21–7.19 (m, 2H), 5.32 (ddd, J = 3.0, 5.5,
3
3
) δ 7.31–7.28 (m, 2H),
1
1
1
7
3
9
2
.0 Hz, 1H), 3.71 (s, 3H), 3.45 (dd, J = 2.0, 7.0 Hz, 1H), 3.39 (s, 10.0 Hz, 1H), 3.42 (s, 3H), 3.40 (s, 3H), 3.38–3.35 (m, 1H), 3.26
H), 3.37 (q, J = 2.5 Hz, 1H), 3.33 (s, 3H), 3.02 (ddd, J = 1.5, 6.0, (qd, J = 3.0, 5.5 Hz, 1H), 3.21 (ddd, J = 2.0, 4.5, 7.0 Hz, 1H),
.5 Hz, 1H), 2.26 (ddd, J = 3.0, 10.0, 13.0 Hz, 1H), 1.95 (ddd, J = 2.57 (ddd, J = 2.5, 10.5, 14.0 Hz, 1H), 1.89 (ddd, J = 3.0, 7.5,
1
3
13
.5, 6.0, 13.0 Hz, 1H) ppm; C NMR (125 MHz, CDCl3) 13.5 Hz, 1H) ppm; C NMR (125 MHz, CDCl ) δ 200.5, 165.2 &
3
δ 198.7, 172.7, 133.9, 95.8, 93.9, 53.3, 52.4, 52.0, 51.0, 50.1, 163.0 (C-5), 143.2, 128.7, 127.7, 127.0, 96.9, 93.6, 53.1, 50.7,
+
3
3
8.7, 24.8 ppm; HRMS (ESI+) calcd for C12
88.9856. Found: 388.9854.
H15IO
5
Na [M + Na] : 50.1, 42.4 & 42.2 (C-4), 39.7, 30.1 ppm; HRMS (ESI+) calcd for
+
C H FO Na [M + Na] : 299.1059. Found: 299.1069.
1
6
17
3
(
1S*,4R*,7S*)-3,3-Dimethoxy-5-iodo-7-methoxycarbonyl-7-
methylbicyclo[2.2.2]oct-5-en-2-one (11b). Yield 0.342 g (90%) oct-5-en-2-one (13a). Yield 0.130 g (89%) as a white solid: mp
as a yellow solid: mp 88–89 °C; IR (KBr) ν 1737, 1638, 1442, 71–72 °C; IR (KBr) ν 1737, 1611, 1490, 1455, 1326, 1199,
(1S*,4R*,7S*)-5-Chloro-3,3-dimethoxy-7-phenylbicyclo[2.2.2]-
max
max
−1 1
−
1
1
1
382, 1215, 1125, 1049 cm ; H NMR (500 MHz, CDCl
dd, J = 2.0, 7.0 Hz, 1H), 3.70 (s, 3H), 3.39 (s, 3H), 3.35 (s, 3H), (m, 3H), 7.16–7.14 (m, 2H), 6.04 (dd, J = 2.5, 6.5 Hz, 1H), 3.42
.30 (d, J = 6.5 Hz, 2H), 2.45 (dd, J = 3.5, 13.5 Hz, 1H), 1.84 (dd, (s, 3H), 3.41 (s, 3H), 3.40–3.38 (m, 1H), 3.33–3.31 (m, 1H), 3.27
J = 3.0, 14.0 Hz, 1H), 1.29 (s, 3H) ppm; C NMR (125 MHz, (dd, J = 2.0, 7.0 Hz, 1H), 2.58 (ddd, J = 3.0, 9.5, 13.0 Hz, 1H),
CDCl
3 3
) δ 6.63 1136, 1098, 1064 cm ; H NMR (500 MHz, CDCl ) δ 7.31–7.21
(
3
1
3
1
3
3
) δ 200.0, 175.6, 135.8, 95.7, 94.1, 59.8, 52.6, 52.2, 51.0, 1.85 (ddd, J = 2.5, 6.5, 13.5 Hz, 1H) ppm; C NMR (125 MHz,
4
9.8, 46.3, 32.0, 25.2 ppm. HRMS (ESI+) calcd for C H IO Na CDCl ) δ 200.3, 143.2, 136.8, 128.8, 127.6, 127.1, 120.4, 93.6,
1
3
17
5
3
+
[
M + Na] : 403.0018. Found: 403.0023.
1S*,4R*,7S*)-7-Acetyl-3,3-dimethoxy-5-iodobicyclo[2.2.2]oct-
-en-2-one (11c). Yield 0.298 g (85%) as a white solid: mp 317.0734. Found: 315.0769 and 317.0738.
4–76 °C; IR (KBr) νmax 1738, 1642, 1457, 1364, 1267, 1135, (1R*,2R*,6R*,7R*)-11-Chloro-8,8-dimethoxy-3-oxatricyclo-
56.1, 50.8, 50.3, 48.3, 40.1, 30.2 ppm; HRMS (ESI+) calcd for
+
+
(
16 3
C H17ClO Na [M + Na] and [M + 2 + Na] : 315.0763 and
5
7
1
7
3
3
1
1
067 cm−
1
;
1
H NMR (500 MHz, CDCl
3
) δ 6.58 (dd, J = 2.0, [5.2.2.0 ]undec-10-en-9-one (13b). Yield 0.134 g (90%) as a
1740, 1598, 1498, 1452,
2,6
.0 Hz, 1H), 3.41–3.40 (m, 1H), 3.39 (s, 3H), 3.38–3.37 (m, 1H), brown viscous liquid; IR (KBr) ν
max
1 1
.35 (s, 3H), 3.05 (ddd, J = 1.0, 6.5, 9.5 Hz, 1H), 2.24 (ddd, J = 1351, 1271, 1224, 1097, 1043 cm− ; H NMR (500 MHz, CDCl
)
3
.0, 10.0, 13.0 Hz, 1H), 2.17 (s, 3H), 1.84 (ddd, J = 2.5, 6.0, δ 6.03–6.01 (m, 1H), 4.33 (dd, J = 3.0, 8.0 Hz, 1H), 3.95 (dt, J =
3.0 Hz, 1H) ppm; C NMR (125 MHz, CDCl ) δ 205.0, 199.1, 3.0, 8.0 Hz, 1H), 3.62–3.57 (m, 2H), 3.38 (s, 3H), 3.35 (s, 3H),
1
3
3
34.1, 94.8, 94.2, 52.8, 52.1, 51.0, 50.2, 46.8, 28.2, 24.0 ppm; 3.27 (apparent t, J = 2.5, 1H), 3.00 (dq, J = 3.0, 8.5 Hz, 1H), 2.15
+
HRMS (ESI+) calcd for C12
Found: 372.9906.
H
15IO
4
Na [M + Na] : 372.9913. (dddd, J = 3.0, 6.5, 9.5, 12.5 Hz, 1H), 1.76–1.68 (m, 1H) ppm;
1
3
C NMR (125 MHz, CDCl ) δ 199.5, 134.6, 120.8, 93.0, 78.1,
3
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6
9.1, 56.6, 51.3, 50.8, 50.0, 39.2, 30.0 ppm; HRMS (ESI+) calcd CDCl
3
) δ 199.8, 143.2, 128.7, 127.5, 127.1, 125.2, 124.9, 93.8,
+
+
for C H ClO Na [M + Na] and [M + 2 + Na] : 281.0556 and 57.3, 50.8, 50.2, 50.1, 40.0, 30.3 ppm; HRMS (ESI+) calcd for
12
15
4
+
+
2
83.0526. Found: 281.0570 and 283.0522.
1S*,4R*,7S*)-5-Chloro-3,3-dimethoxy-7-ethoxybicyclo[2.2.2]-
16 3
C H17BrO Na [M + Na] and [M + 2 + Na] : 359.0258 and
(
361.0237. Found: 359.0255 and 361.0233.
oct-5-en-2-one (13c). Yield 0.098 g (75%) as a yellowish viscous
(1R*,2R*,6R*,7R*)-11-Bromo-8,8-dimethoxy-3-oxatricyclo-
[5.2.2.0 ]undec-10-en-9-one (14b). Yield 0.144 g (95%) as a
liquid; IR (KBr) νmax 1742, 1619, 1449, 1361, 1105, 1029 cm−
1
;
2,6
1
3
H NMR (500 MHz, CDCl ) δ 5.99 (dd, J = 1.5, 6.5 Hz, 1H), liquid; IR (KBr) νmax 1737, 1612, 1449, 1219, 1143, 1094,
.97–3.94 (m, 1H), 3.57 (dd, J = 2.5, 6.5 Hz, 1H), 3.52–3.39 (m, 1050 cm− ; H NMR (500 MHz, CDCl ) δ 6.26 (ddd, J = 0.5, 2.0,
1 1
3
2
3
H), 3.37 (s, 3H), 3.31 (s, 3H), 3.16 (q, J = 3.0 Hz, 1H), 2.46 6.5, 1H), 4.33 (dd, J = 3.0, 8.0 Hz, 1H), 3.95 (dt, J = 3.5, 8.0 Hz,
(
1
ddd, J = 2.5, 8.0, 13.5 Hz, 1H), 1.56 (td, J = 3.5, 13.5 Hz, 1H), 1H), 3.60 (ddd, J = 2.5, 8.5, 11.5 Hz, 1H), 3.56 (dd, J = 3.5,
.17 (t, J = 7.0 Hz, 3H) ppm; C NMR (125 MHz, CDCl3) 6.5 Hz, 1H), 3.38 (s, 3H), 3.37–3.36 (m, 1H), 3.34 (s, 3H), 3.04
1
3
δ 199.8, 136.0, 119.4, 93.4, 74.1, 64.4, 54.6, 50.8, 49.9, 46.9, (ddd, J = 2.5, 8.0, 17.0 Hz, 1H), 2.14 (dddd, J = 3.0, 6.5, 9.5,
3
0.6, 15.3 ppm; HRMS (ESI+) calcd for
C
12
H
17ClO
4
Na 12.5 Hz, 1H), 1.81 (dddd, J = 2.5, 9.0, 12.0, 15.5 Hz, 1H) ppm;
+
13
[M + Na] : 283.0713. Found: 283.0713.
C NMR (125 MHz, CDCl ) δ 199.2, 125.6, 122.5, 93.3, 78.0,
3
(
1S*,4R*,7S*)-7-Butyloxy-5-chloro-3,3-dimethoxybicyclo[2.2.2]- 69.2, 56.9, 52.6, 50.9, 50.1, 39.6, 29.8 ppm; HRMS (ESI+) calcd
+
+
4
oct-5-en-2-one (13d). Yield 0.118 g (82%) as a white liquid; for C12H15BrO Na [M + Na] and [M + 2 + Na] : 325.0051 and
IR (KBr) ν
H NMR (500 MHz, CDCl
1743, 1621, 1464, 1357, 1276, 1107, 1057 cm−
1
;
327.0031. Found: 325.0050 and 327.0033.
max
1
3
) δ 5.97 (dd, J = 2.0, 6.5 Hz, 1H),
(1S*,4R*,7S*)-5-Bromo-3,3-dimethoxy-7-ethoxybicyclo[2.2.2]-
3
1
3
3
0
.95–3.92 (m, 1H), 3.56 (dd, J = 2.5, 6.5 Hz, 1H), 3.44–3.40 (m, oct-5-en-2-one (14c). Yield 0.114 g (75%) as a white liquid; IR
H), 3.36 (s, 3H), 3.35–3.33 (m, 1H), 3.32 (s, 3H), 3.15 (q, J = (KBr) νmax 1742, 1613, 1448, 1273, 1369, 1104 cm− ; H NMR
.0 Hz, 1H), 2.45 (ddd, J = 2.5, 8.0, 13.5 Hz, 1H), 1.55 (ddd, J = (500 MHz, CDCl ) δ 6.21 (d, J = 6.5 Hz, 1H), 3.96–3.94 (m, 1H),
.5, 6.5, 13.5 Hz, 1H), 1.52–1.48 (m, 2H), 1.37–1.29 (m, 2H), 3.55–3.53 (m, 1H), 3.51–3.47 (m, 1H), 3.44–3.39 (m, 1H), 3.37
1 1
3
1
3
.95 (t, J = 3.0 Hz, 3H) ppm; C NMR (125 MHz, CDCl3) (s, 3H), 3.31 (s, 3H), 3.25–3.23 (m, 1H), 2.45 (ddd, J = 2.5, 8.5,
δ 200.0, 136.0, 119.4, 93.5, 74.3, 68.9, 54.6, 50.8, 49.9, 46.9, 13.5 Hz, 1H), 1.55 (td, J = 3.0, 13.5 Hz, 1H), 1.17 (t, J = 7.0 Hz,
1
3
3
1.7, 30.6, 19.3, 13.8 ppm; HRMS (ESI+) calcd for 3H) ppm; C NMR (125 MHz, CDCl
3
); δ 199.5, 124.0, 123.9,
+
+
C H ClO Na [M + Na] and [M + 2 + Na] : 311.1026 and 93.7, 74.0, 64.4, 55.8, 50.9, 50.0, 48.6, 30.7, 15.3 ppm; HRMS
1
4
21
4
+
+
3
13.0997. Found: 311.1029 and 313.1001.
1R*,4R*,7S*)-5-Chloro-3,3-dimethoxy-7-phenylthiobicyclo- 327.0207 and 329.0187. Found: 327.0212 and 329.0204.
2.2.2]oct-5-en-2-one (13e). Yield 0.134 g (83%) as a yellow (1S*,4R*,7S*)-5-Bromo-7-butyloxy-3,3-dimethoxybicyclo[2.2.2]-
semi-solid; IR (KBr) νmax 1736, 1606, 1442, 1314, 1250, 1207, oct-5-en-2-one (14d). Yield 0.142 g (85%) as a white liquid;
4
(ESI+) calcd for C12H17BrO Na [M + Na] and [M + 2 + Na] :
(
[
−
1
1
) δ 7.51–7.41 IR (KBr) νmax 1743, 1614, 1460, 1360, 1105 cm−1
1
1
134, 1089, 1055 cm ; H NMR (500 MHz, CDCl
3
; H NMR
(
m, 2H), 7.36–7.28 (m, 3H), 6.10 (apparent dd, J = 3.0, 7.0 Hz, (500 MHz, CDCl ) δ 6.20 (dd, J = 2.0, 6.5 Hz, 1H), 3.94–3.91 (m,
3
1
H), 3.68–3.62 (m, 1H), 3.38 (s, 3H), 3.36 (s, 3H), 3.28 (appar- 1H), 3.54 (dd, J = 2.5, 7.0 Hz, 1H), 3.43–3.40 (m, 1H), 3.37 (s,
ent dd, J = 2.5, 6.5 Hz, 1H), 3.21 (d, J = 2.5 Hz, 1H), 2.60 (ddd, 3H), 3.36–3.33 (m, 1H), 3.31 (s, 3H), 3.24 (q, J = 3.0 Hz, 1H),
J = 2.5, 9.0, 13.0 Hz, 1H), 1.49 (ddd, J = 2.5, 5.0, 13.5 Hz, 1H) 2.44 (ddd, J = 3.0, 8.0, 13.5 Hz, 1H), 1.54 (ddd, J = 3.0, 6.5, 13.5
1
3
ppm; C NMR (125 MHz, CDCl
1
3
) δ 199.4, 136.5, 133.9, 132.1, Hz, 1H), 1.52–1.48 (m, 2H), 1.35–1.30 (m, 2H), 0.90 (t, J =
1
3
29.3, 127.8, 121.0, 93.6, 53.6, 50.8, 50.2, 47.6, 42.2, 28.8 ppm; 7.5 Hz, 3H) ppm; C NMR (125 MHz, CDCl
HRMS (ESI+) calcd for C H ClO SNa [M + Na] : 347.0479. 123.9, 93.7, 74.1, 68.9, 55.8, 50.9, 49.9, 48.6, 31.8, 30.7, 19.3,
Found: 347.0429.
1R*,4S*,8RS)-2-Chloro-6,6-dimethoxy-5-oxobicyclo[2.2.2]oct- [M + 2 + Na] : 355.0520 and 357.0499. Found: 355.0509 and
-en-8-yl acetate (13f). Yield 0.096 g (70%) as a yellow liquid; 357.0490.
3
) δ 199.6, 124.1,
+
1
6
17
3
+
4
13.8 ppm; HRMS (ESI+) calcd for C14H21BrO Na [M + Na] and
+
(
2
−
1
1
IR (KBr) νmax 2946, 1744, 1448, 1367, 1099 cm
;
H NMR
(1R*,4R*,7S*)-5-Bromo-3,3-dimethoxy-7-phenylthiobicyclo-
(
500 MHz, CDCl
3
) δ 6.16 (dd, J = 2.5, 7.0 Hz, 1H), 6.02 (dd, J = [2.2.2]oct-5-en-2-one (14e). Yield 0.142 g (77%) as a yellow
2
6
3
3
1
.0, 6.5 Hz, 1H), 5.23–5.20 (m, 1H), 3.90 (s, 3H), 3.83 (d, J = crystalline solid: mp 110–112 °C; IR (KBr) ν 1736, 1593,
max
.5 Hz, 1H), 3.51 (dd, J = 2.5, 6.5 Hz, 1H), 3.42–3.39 (m, 1H), 1439, 1126, 1087, 1055, 1015 cm− ; H NMR (500 MHz, CDCl
1
1
)
3
.39 (s, 3H), 3.32 (s, 3H), 3.30 (d, J = 5.0 Hz, 1H), 3.20 (q, J = δ 7.42–7.28 (m, 5H), 6.33 (dd, J = 2.0, 7.0 Hz, 1H), 3.66–3.60
.0 Hz, 1H), 2.66 (ddd, J = 3.0, 8.5, 14.5 Hz, 1H), 2.04 (s, 3H), (m, 1H), 3.38 (s, 3H), 3.33 (s, 3H), 3.30 (q, J = 2.5 Hz, 1H), 3.26
.57 (ddd, J = 3.5, 7.0, 14.0 Hz, 1H) ppm.
1S*,4R*,7S*)-5-Bromo-3,3-dimethoxy-7-phenylbicyclo[2.2.2]- 1.49 (ddd, J = 3.0, 6.0, 14.0 Hz, 1H) ppm; C NMR (125 MHz,
oct-5-en-2-one (14a). Yield 0.125 g (74%) as a white solid: mp CDCl ) δ 199.2, 133.9, 132.1, 129.1, 127.9, 125.6, 124.4, 93.8,
(dd, J = 2.0, 6.5 Hz, 1H), 2.60 (ddd, J = 3.0, 9.5, 14.0 Hz, 1H),
1
3
(
3
8
1
7–88 °C; IR (KBr) νmax 1737, 1605, 1485, 1453, 1323, 1198, 54.7, 50.8, 50.2, 49.3, 41.9, 28.9 ppm; HRMS (ESI+) calcd for
−
1
1
+
+
134, 1094, 1064 cm ; H NMR (500 MHz, CDCl
3
) δ 7.31–7.28
16 3
C H17SBrO Na [M + Na] and [M + 2 + Na] : 390.9979 and
(
7
(
1
m, 2H), 7.25–7.22 (m, 1H), 7.16–7.14 (m, 2H), 6.27 (dd, J = 2.5, 392.9958. Found: 390.9961 and 392.9931.
.0 Hz, 1H), 3.42 (s, 3H), 3.40 (s, 3H), 3.35–3.30 (m, 2H), 3.25 (1R*,4S*,8RS)-2-Bromo-6,6-dimethoxy-5-oxobicyclo[2.2.2]oct-
dd, J = 1.5, 6.5 Hz, 1H), 2.56 (ddd, J = 3.0, 9.5, 13.0 Hz, 1H), 2-en-8-yl acetate (14f). Yield 0.144 g (90%) as a viscous liquid;
1
3
−1
1
.84 (ddd, J = 2.5, 6.5, 13.5 Hz, 1H) ppm; C NMR (125 MHz, IR (KBr) νmax 2947, 1740, 1441, 1321, 1024 cm ; H NMR
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(
500 MHz, CDCl
3
) δ 6.26 (dd, J = 1.5, 7.0 Hz, 1H), 6.22 (dd, J = 3.66–3.24 (m, 1H), 3.41 (s, 3H), 3.37–3.35 (m, 1H), 3.35 (s, 3H),
2
6
3
2
1
.5, 7.5 Hz, 1H), 5.20 (m, 1H), 5.06 (m, 1H), 3.48 (dd, J = 2.5, 3.20 (dd, J = 2.0, 6.5 Hz, 1H), 2.54 (ddd, J = 3.0, 9.5, 17.0 Hz,
1
3
.5 Hz, 1H), 3.40 (s, 3H), 3.39 (s, 3H), 3.37 (s, 3H), 3.31 (s, 3H), 1H), 1.48 (ddd, J = 3.0, 5.5, 17.0 Hz, 1H) ppm; C NMR
.30 (m, 1H), 3.28 (m, 1H), 2.65 (ddd, J = 3.0, 8.5, 14.0 Hz, 1H), (125 MHz, CDCl ) δ 199.0, 134.5, 133.9, 132.1, 129.3, 127.8,
.25 (ddd, J = 3.5, 10.0, 14.5 Hz, 1H), 2.04 (s, 3H), 2.03 (s, 3H), 95.3, 94.0, 56.2, 52.3, 51.1, 50.2, 41.8, 28.7 ppm; HRMS (ESI+)
3
+
.94 (ddd, J = 2.0, 6.5, 14.0 Hz, 1H), 1.57 (ddd, J = 3.5, 6.5, 14.0 calcd for C16
(1R*,4S*,8RS)-2-Iodo-6,6-dimethoxy-5-oxobicyclo[2.2.2]oct-
1S*,4R*,7S*)-3,3-Dimethoxy-5-iodo-7-phenylbicyclo[2.2.2]- 2-en-8-yl acetate (15f). Yield 0.165 g (90%) as a viscous liquid;
3
H17IO SNa [M + Na] : 438.9835. Found: 438.9812.
Hz, 1H) ppm.
(
oct-5-en-2-one (15a). Yield 0.144 g (75%) as a white solid: IR (KBr) νmax 2946, 1742, 1436, 1370, 1097 cm−
mp 68–69 °C; IR (KBr) νmax 1736, 1593, 1452, 1260, 1197, 1133, (500 MHz, CDCl ) δ 6.58 (dd, J = 1.5, 6.5 Hz, 1H), 6.02 (dd, J =
H NMR (500 MHz, CDCl ) δ 7.31–7.22 (m, 3H), 2.0, 6.5 Hz, 1H), 5.20 (m, 1H), 5.04 (m, 1H), 3.40–3.39 (m, 1H),
1
;
1
H NMR
3
091 cm−
;
1
1
1
7
2
3
.15–7.13 (m, 2H), 6.59 (dd, J = 2.0, 7.0 Hz, 1H), 3.45 (q, J = 3.39 (s, 3H), 3.38 (s, 3H), 3.38–3.37 (m, 1H), 3.36 (s, 3H),
.5 Hz, 1H), 3.42 (s, 3H), 3.40 (s, 3H), 3.39–3.35 (m, 1H), 3.15 3.35–3.31 (m, 3H), 3.30 (s, 3H), 2.57 (ddd, J = 2.5, 8.0, 14.0 Hz,
(
1
dd, J = 1.5, 6.5 Hz, 1H), 2.48 (ddd, J = 3.0, 9.5, 13.0 Hz, 1H), 1H), 2.22 (ddd, J = 3.0, 10.0, 14.0 Hz, 1H), 2.04 (s, 3H), 2.03 (s,
.81 (ddd, J = 2.5, 6.5, 13.5 Hz, 1H) ppm; C NMR (125 MHz, 3H), 1.87 (ddd, J = 2.5, 5.0, 14.5 Hz, 1H), 1.53 (ddd, J = 3.5, 7.0,
1
3
CDCl
3
) δ 199.6, 143.3, 134.2, 128.7, 127.5, 127.0, 95.9, 94.0, 14.5 Hz, 1H) ppm.
5
C
8.8, 53.1, 51.0, 50.2, 39.8, 30.1 ppm; HRMS (ESI+) calcd for
+
16
H
3
17IO Na [M + Na] : 407.0120. Found: 407.0119.
(
1R*,2R*,6R*,7R*)-8,8-Dimethoxy-11-iodo-3-oxatricyclo-
2
,6
Acknowledgements
[
5.2.2.0 ]undec-10-en-9-one (15b). Yield 0.149 g (85%) as a
white solid: mp 72–73 °C; IR (KBr) νmax 1735, 1590, 1451,
Thanks are due to Mr Virendra Singh Rajora for carrying out a
couple of reactions presented herein. We are grateful to DST,
New Delhi for financial support (research grant no. SR/S1/
OC-38/2011) and HRMS facility (DST-FIST program). SRS and
SKRP thank CSIR, New Delhi for the award of research
fellowships.
1 1
1
349, 1275, 1139 cm− ; H NMR (500 MHz, CDCl
3
) δ 6.61 (dd,
J = 1.0, 6.5 Hz, 1H), 4.35 (dd, J = 3.0, 8.0 Hz, 1H), 3.95 (dt, J =
.5, 8.5 Hz, 1H), 3.63–3.59 (m, 1H), 3.51 (dd, J = 3.0, 6.5 Hz,
H), 3.48–3.47 (m, 1H), 3.38 (s, 3H), 3.33 (s, 3H), 3.12–3.06
m, 1H), 2.13 (dddd, J = 3.5, 6.5, 10.0, 13.0 Hz, 1H), 1.96–1.87
m, 1H) ppm; C NMR (125 MHz, CDCl
3
1
(
(
1
3
3
) δ 199.0, 134.5, 93.6,
9
3.1, 77.9, 69.3, 58.5, 54.7, 51.2, 50.0, 39.9, 29.4 ppm; HRMS
+
(ESI+) calcd for C H IO Na [M + Na] : 372.9912. Found:
12 15 4
3
72.9908.
1S*,4R*,7S*)-3,3-Dimethoxy-7-ethoxy-5-iodobicyclo[2.2.2]oct-
Notes and references
(
5
-en-2-one (15c). Yield 0.153 g (87%) as a white viscous liquid;
1 (a) S. P. Roche and J. A. Porco Jr., Angew. Chem., Int. Ed.,
2011, 50, 4068–4093; (b) L. Pouységu, D. Deffieux and
IR (KBr) νmax 1741, 1594, 1447, 1358, 1272, 1103, 1047 cm−
1
;
1
H NMR (500 MHz, CDCl
3
) δ 6.53 (dd, J = 1.5, 7.0 Hz, 1H),
S.
Quideau, Tetrahedron,
2010, 66,
2235–2261;
3
3
.96–3.93 (m, 1H), 3.52–3.39 (m, 3H), 3.37 (s, 3H), 3.30 (s, 3H),
.28–3.27 (m, 1H), 2.38 (ddd, J = 3.0, 8.5, 14.0 Hz, 1H), 1.52
(c) S. Quideau, L. Pouységu and D. Deffieux, Synlett, 2008,
467–495.
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Res., 1999, 32, 324–333.
1
3
(td, J = 3.0, 13.5 Hz, 1H), 1.17 (t, J = 7.0 Hz, 3H) ppm; C NMR
(125 MHz, CDCl ) δ 199.2, 132.8, 94.7, 93.8, 73.8, 64.3, 57.2,
3
5
C
1.3, 51.0, 49.9, 30.4, 15.2 ppm; HRMS (ESI+) calcd for
+
12
H
17IO
4
Na [M + Na] : 375.0069. Found: 375.0060.
(
1S*,4R*,7S*)-7-Butyloxy-3,3-dimethoxy-5-iodobicyclo[2.2.2]-
3 (a) C.-C. Liao, Pure Appl. Chem., 2005, 77, 1221–1234;
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oct-5-en-2-one (15d). Yield 0.167 g (88%) as a viscous liquid;
IR (KBr) νmax 1742, 1596, 1459, 1360, 1268, 1103, 1056 cm−
1
;
1
H NMR (500 MHz, CDCl ) δ 6.52 (dd, J = 1.5, 6.5 Hz, 1H),
3
3
.95–3.90 (m, 1H), 3.45 (dd, J = 2.5, 7.0 Hz, 1H), 3.42–3.39 (m,
H), 3.37 (s, 3H), 3.36–3.30 (m, 1H), 3.30 (s, 3H), 3.27 (q, J =
.0 Hz, 1H), 2.36 (ddd, J = 3.0, 8.0, 14.0 Hz, 1H), 1.53–1.48 (m,
1
3
3
(
5
1
3
H), 1.37–1.30 (m, 2H), 0.90 (t, J = 7.5 Hz, 3H) ppm; C NMR
) δ 199.4, 132.9, 94.7, 93.9, 74.0, 68.9, 57.2,
1.4, 51.1, 49.9, 31.7, 30.5, 19.3, 13.8 ppm; HRMS (ESI+) calcd
125 MHz, CDCl
3
+
for C14
1R*,4R*,7S*)-3,3-Dimethoxy-5-iodo-7-phenylthiobicyclo[2.2.2]-
oct-5-en-2-one (15e). Yield 0.189 g (91%) as a yellow solid: mp
4
H21IO Na [M + Na] : 403.0382. Found: 403.0377.
(
1
1
01–103 °C; IR (KBr) νmax 1726, 1583, 1441, 1310, 1252, 1205,
131, 1078, 1051 cm ; H NMR (500 MHz, CDCl ) δ 7.43–7.40
3
8 D.-S. Hsu and C.-C. Liao, Org. Lett., 2007, 9, 4563–4565.
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2008, 73, 2554–2563.
−
1 1
(m, 2H), 7.37–7.30 (m, 3H), 6.66 (dd, J = 1.5, 6.5 Hz, 1H),
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5668 | Org. Biomol. Chem., 2014, 12, 5656–5668
This journal is © The Royal Society of Chemistry 2014